Dual Characteristics of Novel HER2 Kinase Domain Mutations in Response to HER2-Targeted Therapies in Human Breast Cancer

Zuo, Wenbao; Jiang, Yi; Wang, Yu Jie; Xu, Xiao; Hu, Xin; Liu, Guang Yu; Wu, Jiong; Di, Gen-Hong; Yu, Ke; Shao, Zhi Ming

doi:10.1158/1078-0432.ccr-15-3036

Cited by 63 publications

(76 citation statements)

References 42 publications

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“…To date, HER2 missense mutations have been reported by TCGA in ~3% of breast cancer patients with primary HER2+ tumors (results based on cBioPortal) (22, 23). A similar rate of HER2 mutations (2.3%) was also recently reported in the study by Zuo et al in a large cohort of 910 HER2+ primary breast tumors (47). The role of HER2 mutations in acquired resistance to HER2-targeted therapies in HER2+ breast cancer, however, still remains unclear.…”

Section: Discussionsupporting

confidence: 86%

“…Additionally, the study by Zuo et al analyzed 18 pairs of primary and metastatic lesions, 16 of which had received 1 year of adjuvant T treatment, and observed that the drug-resistant HER2 L755S mutation was present in 3/18 metastatic lesions but not in any of the paired primary tumors. Interestingly, a second close mutation, HER2 K753E, which also confers preclinical resistance to L and T, also emerged in 2 of these 18 metastatic lesions (47). This suggests that these two HER2 mutations are associated with clinically acquired resistance to T. Through targeted sequencing of 76 HER2+ primary invasive carcinomas, Boulbes et al (49) identified 12 missense mutations in the HER family kinase domain, including 3 in the HER2 kinase domain (but excluding the L755S variant) that are associated with aggressiveness of the tumor and resistance to T-based therapy in the metastatic setting.…”

Section: Discussionmentioning

confidence: 99%

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HER2 Reactivation through Acquisition of the HER2 L755S Mutation as a Mechanism of Acquired Resistance to HER2-targeted Therapy in HER2+ Breast Cancer

Angelis

Burke

et al. 2017

Clinical Cancer Research

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Purpose Resistance to anti-HER2 therapies in HER2+ breast cancer can occur through activation of alternative survival pathways or reactivation of the HER signaling network. Here we employed BT474 parental and treatment-resistant cell line models to investigate a mechanism by which HER2+ breast cancer can reactivate the HER network under potent HER2-targeted therapies. Experimental Design Resistant derivatives to lapatinib (L), trastuzumab (T), or the combination (LR/TR/LTR) were developed independently from two independent estrogen receptor ER+/HER2+ BT474 cell lines (AZ/ATCC). Two derivatives resistant to the L-containing regimens (BT474/AZ-LR and BT474/ATCC-LTR lines) that showed HER2 reactivation at the time of resistance were subjected to massive parallel sequencing and compared to parental lines. Ectopic expression and mutant-specific siRNA interference were applied to analyze the mutation functionally. In vitro and in vivo experiments were performed to test alternative therapies for mutant HER2 inhibition. Results Genomic analyses revealed that the HER2L755S mutation was the only common somatic mutation gained in the BT474/AZ-LR and BT474/ATCC-LTR lines. Ectopic expression of HER2L755S induced acquired L resistance in the BT474/AZ, SK-BR-3, and AU565 parental cell lines. HER2L755S-specific siRNA knockdown reversed the resistance in BT474/AZ-LR and BT474/ATCC-LTR lines. The HER1/2 irreversible inhibitors afatinib and neratinib substantially inhibited both resistant cell growth and the HER2 and downstream AKT/MAPK signaling driven by HER2L755S in vitro and in vivo. Conclusion HER2 reactivation through acquisition of the HER2L755S mutation was identified as a mechanism of acquired resistance to L-containing HER2-targeted therapy in preclinical HER2-amplified breast cancer models, which can be overcome by irreversible HER1/2 inhibitors.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

HER2 Reactivation through Acquisition of the HER2 L755S Mutation as a Mechanism of Acquired Resistance to HER2-targeted Therapy in HER2+ Breast Cancer

Angelis

Burke

et al. 2017

Clinical Cancer Research

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“…In this series, endocrine resistance was successfully reversed in 1 patient with the addition of neratinib. In HER2-amplified cancers, acquisition of activating HER2 mutations has also been reported by multiple groups as a potential resistance mechanism to HER2 therapy (35,36). Interestingly, we have previously shown that at least a subset of these acquired HER2 mutations in HER2-positive breast cancers retain sensitivity to neratinib, despite conferring resistance to HER2-directed monoclonal antibodies and reversible kinase inhibitors (11).…”

Section: Discussionmentioning

confidence: 54%

Efficacy and Determinants of Response to HER Kinase Inhibition in HER2-Mutant Metastatic Breast Cancer

et al. 2020

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HER2 mutations defi ne a subset of metastatic breast cancers with a unique mechanism of oncogenic addiction to HER2 signaling. We explored activity of the irreversi ble pan-HER kinase inhibitor neratinib, alone or with fulvestrant, in 81 patients with HER2mutant metastatic breast cancer. Overall response rate was similar with or without estrogen receptor (ER) blockade. By comparison, progression-free survival and duration of response appeared longer in ER + patients receiving combination therapy, although the study was not designed for direct comparison. Preexistent concurrent activating HER2 or HER3 alterations were associated with poor treatment outcome. Similarly, acquisition of multiple HER2 -activating events , as well as gatekeeper alterations, were observed at disease progression in a high proportion of patients deriving clinical benefi t from neratinib. Collectively, these data defi ne HER2 mutations as a therapeutic target in breast cancer and suggest that coexistence of additional HER signaling alterations may promote both de novo and acquired resistance to neratinib. SIGNIFICANCE: HER2 mutations defi ne a targetable breast cancer subset, although sensitivity to irreversible HER kinase inhibition appears to be modifi ed by the presence of concurrent activating genomic events in the pathway. These fi ndings have implications for potential future combinatorial approaches and broader therapeutic development for this genomically defi ned subset of breast cancer.

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“…and Zuo et al . reported the presence of multiple novel HER family mutations in both primary and metastatic HER2-positive breast tumors(23, 24). Boulbes et al .…”

Section: Oncogenic Her2 Addictionmentioning

confidence: 99%

“…Interestingly, the Zuo et al . study that analyzed 18 pairs of primary and metastatic lesions, which included 16 pairs from patients who received one year of trastuzumab, showed that the L755S and the nearby K753E HER2 mutations appeared in three and two metastatic lesions, respectively(24). Collectively, these intriguing results suggest that rare pre-existing or acquired HER2 mutations emerge as a mechanism of acquired resistance, similar to the events of ESR1 constitutive active mutations recently described in endocrine resistant metastatic breast cancer(26).…”

Section: Oncogenic Her2 Addictionmentioning

confidence: 99%

De-escalation of treatment in HER2-positive breast cancer: Determinants of response and mechanisms of resistance

et al. 2017

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Summary Overexpression and/or gene amplification of HER2, a crucial member of the HER family of four receptors, occur in about 15–20% of breast cancers and define an aggressive subtype of the disease. Activated HER homo and heterodimers govern a complex and redundant downstream signaling network that regulates cell survival and metastasis. Despite treatment with effective HER2-targeted therapies, many HER2-positive tumors fail to respond, or initially respond but eventually develop resistance. One of the upfront reasons for this treatment failure is failure to accurately select the tumors that are truly dependent on HER2 for survival and so would benefit the most from HER2-targeted therapy. In these truly HER2-addicted tumors (i.e. physiologically dependent), resistance could be the result of an incomplete inhibition of signaling at the HER receptor layer. In this regard, preclinical and clinical studies have documented the superiority of combination anti-HER2 therapy over single agent therapy to achieve a more comprehensive inhibition of the various HER receptor dimers. HER2 can be further activated or reactivated by mutations or other alterations in HER2 itself, or in other HER family members. Even when a complete and sustained HER inhibition is achieved, resistance to anti-HER therapy can arise by other somewhat dominant mechanisms, including preexisting or emerging alternative signaling pathways such as the estrogen receptor, deregulated downstream signaling components, especially of the PI3K pathway, and the tumor immune microenvironment. Most of the clinical trials that have investigated the efficacy of anti-HER2 therapies took place in the background of aggressive chemotherapy regimens, thus confounding the identification of key factors of resistance to the anti-HER2 treatments. Recent studies, however, have suggested that some HER2-amplified tumors may benefit from anti-HER2 therapy combined with only single chemotherapy agent or in the absence of any chemotherapy. This de-escalation approach, a promising therapeutic strategy, is currently being explored in the clinic. In this review, we summarize the major molecular determinants that play a crucial role in influencing tumor response and resistance to HER2-targeted therapy, and discuss the growing need for patient stratification in order to facilitate the development of de-escalation strategies using HER2-targeted therapy alone with no chemotherapy.

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Dual Characteristics of Novel HER2 Kinase Domain Mutations in Response to HER2-Targeted Therapies in Human Breast Cancer

Cited by 63 publications

References 42 publications

HER2 Reactivation through Acquisition of the HER2 L755S Mutation as a Mechanism of Acquired Resistance to HER2-targeted Therapy in HER2+ Breast Cancer

HER2 Reactivation through Acquisition of the HER2 L755S Mutation as a Mechanism of Acquired Resistance to HER2-targeted Therapy in HER2+ Breast Cancer

Efficacy and Determinants of Response to HER Kinase Inhibition in HER2-Mutant Metastatic Breast Cancer

De-escalation of treatment in HER2-positive breast cancer: Determinants of response and mechanisms of resistance

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